Renin is a critical protein in the angiotensin system which control vasoconstriction/dilation, as it is the first and rate-limiting enzyme in the formation of the vasoactive octapeptide known as angiotensin II. Angiotensin II is known to be a potent pressor substance, i.e., a substance which can induce a significant increase in blood pressure, and is believed to act by causing the constriction of blood vessels and the release of the sodium-retaining hormone aldosterone from the adrenal gland. Renin is known to be active in in vivo in specifically cleaving angiotensinogen, giving rise to the decapeptide intermediate angiotensin I, which is in turn converted (via "converting enzyme") to angiotensin II.
The renin-angiotensinogen system has thus been implicated as a causative factor in certain forms of hypertension and congestive heart failure. The various features of the foregoing angiotensin system offer a number of opportunities for the targeting of therapeutic drugs. Various approaches have, in fact, been tried. A large family of drugs, .beta.-adrenergic inhibitors (also known as .beta.-blockers) have been used extensively, and are known to act, at least in part, by inhibiting renin secretion from the juxtaglomerular cells of the kidney. Angiotensin converting enzyme ("ACE") inhibitors have also been used to inhibit conversion of angiotensin I to angiotensin II; examples of ACE inhibitor drugs include captopril and enalapril. In addition, drugs which interfere directly with angiotensin II action have been developed, including, for example, saralasin, which is a competitive inhibitor of angiotensin II binding.
Many of the currently available drugs for alleviating the adverse effects of the functioning of the renin-angiotensinogen system are unsatisfactory for one reason or another. Efficacy of the drugs is often unpredictable, and unwanted side effects, due to a multiplicity of biological activities in addition to that intended, are frequent. Also, many drugs intended to reduce hypertension cannot be administered orally. This is particularly true with renin inhibitors, many of which have been shown to be active in lowering blood pressure in both animals and humans when administered intravenously or intramuscularly (see, e.g., E. Haber, Hypertension and the Angiotensin System: Therapeutic Approaches, Raven Press 133-145 (1984), and J. P. Gagnol, et al., Abstracts of the International Society of Hypertension, 10:376) (1984), but are not orally active.
Accordingly, the present invention is directed to a novel class of organic compounds which in large part overcome the aforementioned disadvantages of the prior art. In particular, a new class of orally active renin inhibitors is provided.